Aminoalkyl-spirocycloalkanes as analgetic agents

ABSTRACT

1-AMINOALKYL-BENZCYCLOALKANE-2-SPIROCYCLOALIPHATIC COMPOUNDS, E.G. THOSE OF THE FORMULA   (CH2)M&lt;(-(-B-)&gt;C-C(-R)(-ALK-AM)-(1,2-PHENYLENE)-)   ALK=LOWER ALKYLENE AM=AN AMINO GROUP R=H OR OH B=LOWER ALKYLENE OR ALKYLENE M=1-3   ACYL AND 1-DEHYDRO DERIVATIVES, SALTS AND QUATERNARIES THEREOF EXHIBIT ANALGETIC EFFECTS.

United States Patent Oihce 3,657,440 Patented Apr. 18, 1972 3,657,440 AMINOALKYL-SPIROCYCLOALKANES AS ANALGETIC AGENTS Lincoln Harvey Werner, Summit, N.J., assignor to Cilia- Geigy Corporation, Summit, NJ.

N Drawing. Filed Apr. 23, 1968, Ser. No. 723,585 Int. Cl. A61k 27/00 US. Cl. 424-267 2 Claims ABSTRACT OF THE DISCLOSURE 1-aminoalkyl-benzcycloalkane 2 spirocycloaliphatic compounds, e.g. those of the formula R alk-Am U ad alk =lower alkylene Am an amino group B=lower alkylene or alkylene In: 1-3

acyl and l-dehydro derivatives, salts and quaternaries thereof exhibit analgetic effects.

SUMMARY OF THE INVENTION The present invention concerns and has for its object the provision of new 1-aminoalkyl-benzcycloalkane-2- spirocycloaliphatic compounds, preferably of those having the Formula I DESCRIPTION OF THE PREFERRED EMBODIMENTS The 1,2-phenylene radical Ph is unsubstituted or substituted by one or more than one of the same or of different substituents attached toany of the four positions available for substitution. Such substituents are primarily lower alkyl, e.g. methyl, ethyl, nor i-propyl or -butyl, free, etherified or esterified hydroxy, such as lower alkoxy,

e.g. methoxy, ethoxy, nor i-propoxy or -butoxy, or halo-- geno, e.g. fluoro, chloro or bromo, tri-fluoromethyl, nitro or amino, especially di-lower alkylamino, e.g. dimethylamino or diethylamino. The term flower referred to above or hereinafter in connection with organic radicals or compounds respectively, defines such with up to 7, preferably up to 4, carbon atoms. More particularly Ph stands for 1,2-phenylene, (lower alkyl)-1,2-phcnylene, (hydroxy)-l,2-phenylene, monoor di-(lower alkoXy) 1,2-phenylene, (halogeno)-1,2-phenylene or (trifluoromethyl) -1,2-phenylene.

The lower alkylene portion alk above all represents methylene, 1,2-ethylene or 1,3-propylene, but also rep resents 1,1-ethy1ene, 1,1-, 1,2 or 2,2-propy1ene, 2-methyl1,3-propylene, 1,1-, 1,2-, 1,3-, 2,2- or 2,3-butylene, 1,1-, 1,2-, 1,3-, 2,2- 2,3-, 2,4- or 3,3-pentylene, 1,3- or 2,3- hexylene or 3,5-heptylene.

The lower alkylene or alkenylene radical B preferably represents 1,4-butylene, 1,5-pentylene or 1,5-pent-2-enylene, but also represents 1,4-pentylene, 1,4-, 1,5-, 2,5- or 1,6-hexylene, 1,4-, 1,5, 1,6-, 2,5- or 2,6-heptylene; 1,4- but-2-enylene, 1,4-pent-2-enylene, 1,6-hex-3-enylene or 2,6-hept-3-enylene.

The lower alkylene radical alk above all stands for 1,2-ethylene, 1,2- or 1,3-pro-pylene, but also for Z-methyl- 1,3-propylene, 1,2-, 1,3-, 1,4- or 2,3-butylene, 1,5- or 2,4- pentylene, 1,3-, 1,4- or 1,6-heXylene or 3,5-heptylene.

The amino group Am is a primary, secondary or preferably a tertiary amino group, such as amino, monoor di-lower alkylamino, e.g. methylamino, ethylamino, nor i-propylamino or n-butylamino; dimethylamino, N-rnethyl-N-ethylamino, diethylamino, di-n-propylamino, di-isopropylamino or di-n-butylamino; free or esterified hydroXy-lower alkylamino, N-(hydroXy-lower alkyl)-N-lower alkylamino or di-(hydroxy-lower alkyl)-amino, in which hydroxy is separated from the amino nitrogen by at least 2 carbon atoms, e.g. 2-hydroxyethylamino, 3-hydroxypropylamino, N-(2 hydroxyethyl)-N-methylamino or di-(Z-hydroxyethyl)-amino; monocyclic cycloalkylamino, cycloalkyl-lower alkylamino, N-cycloalkyl-N-lower alkylamino or N-cycloalkyl-lower alkylN-lower alkylamino in which cycloalkyl has preferably 3 to 7 ring carbon atoms, e.g. cyclopropylarnino, cyclopentylamino, cyclohexylamino, cyclopropylmethylamino, Z-cyclopentylethylamino, N-cyclopentyl-N-methylamino, N-cyclohexyl- N-methylamino, N-cycloheXyl-N-ethylamino, N-cyclopentylmethyl-N-ethylamino or N-(2 cyclopentylethyl)-N- methylamino, aralkylamino or N-lower alkyl-N-aralkylamino, in which the aryl, e.g. phenyl, moiety is unsubstituted or substituted as shown for lPh and Ph such as benzylamino, Z-phenethylamino, N-rnethyl-N-benzylamino, N-ethyl-N-benzylarnino or N-ethyl-N-(lor 2-phenethyl)-amino; lower alkyleneimino or free or esterified hydroxy-alkyleneimino, e.g. ethyleneimino, pyrrolidino, 2 methyl-pyrrolidino, piperidino, 2- or 4 methylpiperidino, 3 or 4-hydroxy-piperidino, 3-hydroxymethylpiperidino, 1,6- or 2,5-hexamethyleneimino, 1,7- or 2,6- heptamethyleneimino, lower mono-oxaor thia-alkyleneimino, e.g. morpholino, 3-methyl-morpholino or thiamorpholino, monoaza-lo-wer alkyleneimino, N-lower alkylor free or esterified N-(hydroxy-lower alkyl)-monoaza-lower alkyleneimino, e.g. piperazino, N-methyl, -ethyl-, -n-propyl, -i-propyl, -2-hydroxyethylor -3-hydroxy-propylpiperazino, N-methyl -2-hydroxy-ethylor -n-propyl-3- aza-1,5- or 1,6-hexyleneimino, or N-methyl-4-aza-l,7- or 2,6-heptyleneimino. The amino group Am may also be linked with the alk moiety, so that alk -Am together represents, for example, aza-cycloalkyl, aza-cycloalkyl-lower alkyl, N-lower alkyl-aza-cycloal'kyl or N-lo-wer alkyl-azacycloalkyl-lower alkyl, e.g. 2-or 3-pyrrolidyl, l-rnethylor -ethyl3-pyrrolidyl, 3- or 4-piperidyl or -piperidylmethyl, l-methyl or -ethyl3- or 4-piperidyl or -piperidylmethyl. In the corresponding compounds of Formula I, the heteroatoms in the saturated moieties, e.g. those present in Am, are separated from each other by at least 2 carbon atoms.

Acyl derivatives of the invention are preferably those of the primary or secondary amines or hydroxyalkyl compounds, but may also be those containing an acyloxy group attached to the 1-position. The acyl group therein stands preferably for lower alkanoyl, such as acetyl, propionyl, butyryl or pivalyl, but also for lower alkenoyl, such as acryloyl or methacryloyl, monocyclic carbocyclic aroyl or aryl-lower alkanoyl or -alkenoyl, such as benzoyl, phenylacetyl or cinnamoyl. The quaternaries of the invention are preferably the lower alkyl or aralkyl, e.g. phenyl-lower alkyl quaternaries. Said acyl, alkyl or aralkyl radicals are unsubstituted or substituted, especially in the aromatic portion, as shown for Ph and Phg.

Dehydration of the compounds of Formula I, wherein R is hydroxy, yields the l-dehydro derivatives of the invention, in which the double bond can only extend into alk thus rendering it to the corresponding alkylidene radical.

The compounds of the invention exhibit valuable pharmacological properties. For example, they show analgesic activity as can be demonstrated in animal tests, using advantageously mammals, such as rats, mice, or rabbits as test objects. Such tests can be performed as follows. A radiant heat stimulus is applied to the tail of male mice and the duration of exposure is measured. The end-point is the time at which the animal moves its tail away from the stimulus, which never is applied longer than seconds. Usually ten mice are used for each test and two pre-drug time values are obtained from each animal. Hereupon the compounds of the invention are orally or subcutaneously applied in the form of aqueous solutions or suspensions, for example, in the dosage range between about 1 and 200 mg./kg./day, preferably between about 10 and 100 mg./kg./day, and 15, 30 and/or 60 minutes thereafter two post-drug time values are obtained. To determine the presence of an analgesic effect, the control mean is determined and 3 standard deviations are added; any value above said sum is considered a reactor value, i.e. such indicating analgesia.

In another test system, about 1 mm. holes are drilled to the dental pulp of 2 incisor teeth of anesthetized male rabbits. The following day electrodes are inserted into said holes and a current of about 6 v. is applied to the unanesthetized animal, at which value it usually starts licking, thus providing the control voltage values. Hereupon the compounds of the invention are applied as mentioned above in about the same dosage range and about minutes thereafter again a current is applied until the animal starts licking. In case the voltage ranges above 6 and up to 14 v., analgesia is observed.

Particularly useful are compounds of the Formula I, in which Ph stands for 1,2-phenylene (lower alkyl)-1,2- phenylene (hydroxy)-l,2-phenylene, monoor di-(lower alkoxy)-l,2 phenylene (halogeno) 1,2 phenylene or (trifluoromethyl)-1,2-phenylene, alk is methylene, 1,2 ethylene or 1,3-propylene, B is 1,4-butylene, 1,5-pentylene or 1,5-pent-2-enylene, R is hydrogen or hydroxy, alk is 1,2-ethylene, 1,2- or 1,3-propylene and Am is di-lower alkylamino, lower alkyleneimino, mono-oxa-, -thiaor -aza-lower alkyleneimino or N-lower alkylor N-(hydroxyor lower alkanoyloxy-lower alkyl)-monoaza-lower alkyleneimino, or alk -Am together represents N-lower alkyl-azacycloalkyl or -azacycloalkyl-lower alkyl, wherein the heteroatoms are separated from each other by at least 2 carbon atoms, the 1-dehydro derivatives and therapeutically useful acid addition salts thereof.

Especially valuable are compounds of Formula II in which R is hydrogen or hydroxy, each of R R and R is hydrogen or one or two thereof are methoxy or one thereof is hydroxy or chloro and the others are hydrogen, A is 3-dimethylamino-propyl or -propylidene or l-methyl- 3 or 4-piperidyl or -piperidylmethyl, m is the integer 1 or 2, and n is the integer 4 or 5, and therapeutically useful acid addition salts thereof which, when given at subcutaneous doses between about 15 and 75 Z-Am wherein one of Y and Z is hydrogen or advantageously a metal atom and the other is reactively modified hydroxyalkyl or carboxy-alkyl and reducing any resulting carbonyl derivative, or (2) reacting a tert. aminoalkyl metal compound with a 1-oxo-benzcycloalkane-Z-spiroaliphatic compounds, e.g. those of the formulae Ph/co\ 1 alk wherein Me is an alkali metal or halomagnesium and Am tertiary amino and hydrolyzing the resulting adduct and, if desired, converting any resulting compound into another compound of the invention.

In the starting material shown under item (1) the substituent X or Y is, for example (a) a metallic group, e.g. an alkali metal or halomagnesium, or preferably (b) a reactively esterified hydroxy-alkyl group, such as (halogeno or sulfonyloxy, e.g. chloro, bromo, methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy or tosyloxy)-alkyl or (c) iminoor carbamoylalkyl, nitroor cyano-alkyl. The starting material corresponding to the X mentioned under item (a) is reacted with a reactively esterified, free or salified aminoalkanol, that corresponding to the X mentioned under item (b) is reacted with ammonia or an amine, or an alkali metal or acyl, e.g. phthaloyl, derivative thereof, and that corresponding to the X mentioned under item (0) is reduced. In the condensation of the reactively modified alcohol with ammonia or amines according to (lb), said basic agents are preferably used in excess, in order to neutralize the generated acid. They may, however, also be used in equivalent amounts and in the presence of other condensing agents such as inorganic or organic bases, e.g. alkali metal carbonates or bicarbonates or tertiary nitrogen bases, for example tri-lower alkylamines, N,N-dimethylaniline or pyridine. The reduction of a carbamoyl compound according to item (1c) as well as that of an iminoalkyl compound (Schiifs base or oxime), nitro or cyano compound, is performed in the usual manner, advantageously with the use of complex metal hydrides, such as alkali metal aluminum or borohydrides, e.g. lithium aluminum hydride or sodium borohydride, but also with the use of catalytically activated or nascent hydrogen, e.g. hydrogen in the presence of nickel, platinum or palladium catalysts or hydrogen generated during electrolysis or the reaction of metals with acids or alcohols, e.g. zinc and hydrochloric acid or sodium and ethanol.

The metal compound mentioned under item (2) is preferably a Grignard compound, i.e. Me represents halomagnesium, advantageously chloromagnesiurn, but may also be an alkali metal, e.g. lithium, compound. It is reacted with the oxo compound under the usual conditions, yield, in'g, after hydrolysis with water or aqueous acid or ammonium salt solutions, compounds of the Formula I, in which R is hydroxy or the l-dehydro derivatives.

The compounds of the invention so obtained may be converted into each other according to known methods.

For example, resulting l-dehydro derivatives or compounds in which B contains a double bond or R stands for hydroxy, said group and/or double bond may be red-uctively eliminated, for example with the use of catalytically activated hydrogen. A hydroxy group R may also be eliminated by dehydration, e.g. by pyrolysis or with the use of dehydration agents, e.g. acids, their halides or anhydrides, such as sulfuric acid, acetyl chloride or acetanhydride, to yield the l-dehydro derivatives. Compounds in which Am is a primary or secondary amino group, can be reacted with a reactive ester of a corresponding alcohol, for example, such mentioned above, or can be acylated, for example, with a reactive functional derivative of a corresponding acid, such as a halide or anhydride thereof, or resulting acyl derivatives may be split, for example, with the use of acidic or alkaline hydrolyzing agents, or phthaloyl compounds by hydrazinolysis. Resulting esters may also be hydrolyzed or transesterified or resulting alcohols esterified. Resulting tertiary amines may be quaternized in the usual manner, for example with the use of reactive esters of alcohols, preferably of lower alkanols, but also of aralkanols or resulting quaternaries converted into tertiary amines. 'For example, from benzyl-quaternaries the benzyl residue can be split 01f by hydrogenation.

The compounds of the invention are obtained in the free form or in the form of their salts, depending on the conditions under which the process is carried out; the salts are also included in the present invention. Salts that are obtained can be converted into the free bases in known manner, for example, with alkalis or ion exchangers. Free bases that are obtained can be converted into salts by reaction with inorganic or organic acids, especially those that are suitable for the formation of therapeutically useful salts. Such acids are, for example, mineral acids, e.g. hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, or perchloric acid; aliphatic or aromatic carboxylic or sulfonic acids, e.g. formic, acetic, propionic, succinic, glycollic, lactic, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, pyroracemic, phenylacetic, benzoic, 4- aminobenzoic, anthranilic, 4-hydroxybenzoic, salicylic, 4- aminosalicylic, embonic, nicotinic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonic, halogenbenzenesulfonic, toluenesulfonic, naphthalenesulfonic, sulfanilic or cyclohexylsulfamic acid; methionine, tryptophane, lysine and arginine.

These or other salts of the invention, for example, the picrates, can also be used for purification of the bases obtained; the bases are converted into salts, the salts are separated and the bases are liberated from the salts. In view of the close relationship between the free compounds and the compounds in the form of their salts, whenever a free base is referred to in this context, a corresponding salt is also intended, provided such is possible or appropriate under the circumstances.

The invention further includes any variant of the present process, in which an intermediate product obtainable at any stage of the process is used as starting material and any remaining steps are carried out, or the process is discontinued at any stage thereof, or in which the starting materials are formed under the reaction conditions, or in which the reaction components are used in the form of their salts. For example, the amines or alcohols mentioned above may be used in the form of their alkali metal, e.g. sodium or potassium salts. Mainly those starting materials should be used in the process of the invention that lead to the formation of those compounds indicated above as being specially valuable.

The starting material used is known or, if new, may be prepared according to known methods. For example, that used in reaction (1a) can be obtained by reduction of the l-oxo compound shown under item (2) with sodium borohydride, converting the resulting l-hydroxy compound into a reactive ester thereof, e.g. with the use of thionyl or phosphorus halides, and reacting the l-halogeno compounds either with magnesium or alkali metals or their alloys. The starting material mentioned under items (1b) and (c) is prepared analogous to the method mentioned under item (2), e.g. by reacting an aliphatic metal or Grignard compound, e.g. that of the formula Mealk OCH C H with the same oxo compound, subjecting the resulting adduct to hydrolysis and hydrogenation, in order to eliminate the benzyl group and, if desired, the l-hydroxy group formed also. In the resulting compounds, the l-hydroxyalkyl group can be modified according to methods known per se, for example reactively esterified, e.g. with strong mineral or sulfonic acids using, for example, thionyl halides or phosphorus halides or oxyhalides or sulfonyl halides, e.g. thionyl chloride, phosphorus trior pentabromide or oxychloride, tosyl or brosyl chloride, or oxidized, for example with hydrogen peroxide, heavy metal salts or oxides, e.g. alkali metal chromates or permanganates, chromic or cupric salts, mercuric, manganese or silver oxide, in acidic or alkaline media respectively. Resulting acids may then be converted into their halides, e.g. with the above acid derivatives, which may further be reacted with amines, or resulting aldehydes are converted into oximes or Schifls bases. The l-halogenoalkyl compounds can also be reacted with alkali metal cyanides or silver nitrite in order to obtain the l-cyano or nitro-alkyl starting material. The starting material mentioned under item 2) can be obtained according to the methods described in Compt. Rend. 139, p. 18 05 (1954), J. Org. Chem. 27, p. 3844 (1962), Bull. Soc. Chim. France 1957, p. 346 and 1966, p. 1693.

Starting materials or final products that are mixtures of isomers or racemates, can be separated into the single isomers or racemates by methods in themselves known, e.g. by fractional distillation, crystallization and/or chromatography. Racemic products can likewise be resolved mto the optical antipodes, for example by separatron of diastereomeric salts thereof, e.g. by the fractional crystallization of dor l-tartrates.

The pharmaceutically active compounds of the inventron can be used, for example, for the manufacture of pharmaceutical compositions containing them in conunction or admixture with inorganic or organic, solid or liquid pharmaceutical excipients, suitable for enteral or parenteral administration. Suitable excipients are substances that do not react with the compounds of the invention, for example, water, gelatine, sugars, e.g. lactose, glucose or sucrose, starches, e.g. corn starch or arrowroot, stearic acid or salts thereof, e.g. magnesium or calcium stearate, talc, vegetable fats or oils, gums, alginic acid, benzyl alcohols, glycols and other known excipients. The compositions may be, for example, in solid form as tablets, drages or capsules, or in liquid form as solutions, suspensions or emulsions. They may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/ or buffers. They may fur ther contain other therapeutically valuable substances. Said pharmaceutical compositions are prepared by conventional methods and contain about 0.1 to 75%, more particularly 1 to 50%, of the active ingredient. They are also included within the scope of the present invention.

The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Temperatures are given in degrees Centigrade, and all parts wherever given are parts by weight.

EXAMPLE 1 To the mixture of 2.3 g. magnesium turnings, 20 ml. tetrahydrofuran and 1 ml. ethyl bromide (starter), the solution of 11.4 g. 3-dimethylamino-propyl chloride in 20 ml. tetrahydrofuran is added dropwise while stirring and keeping the mixture under nitrogen. After refluxing for 45 minutes, it is cooled in an ice bath and the solution of 10 g. 1-oxo-1,2,3,4-tetrahydro naphthalene 2 spirocyclohexane in 20 ml. tetrahydrofuran is added dropwise 7 while stirring and stirring is continued for 3 hours at room temperature. After standing overnight, the solution is decanted from some unreacted magnesium and evaporated in vacuo. The residue is taken up in 150 ml. benzene and 75 ml. water are added dropwise while stirring and cooling O in an ice bath. The mixture is warmed up, the supernatant solution decanted from the gelatinous residue, which is triturated three times with 75 ml. warm benzene, O filtered off and washed with 150 ml. warm benzene. The meltmg at 137438 combined organic solutions are washed with water, dried, l0 3 thereof are dlssolved m 50 m 6.thy1 q a filtered and evaporated in vacuo. The residue is recrystal- ISOPTOPaHQI and the sohmon f i Wllh Zed from hexane, to yield the l hydroxy l (3 dimethyl hydrogen chloride in ethyl acetate. The precipitate formed amin0 pmpy1) 12,34 tetrahydronaphthalene 2 spiro 1s filtered off and washed W1th ethyl acetate, t o yield the cyclohexane of the formula corresponding hydrochloride melting at 225 with de- HO (CH2)a-N(CHa)z composmon' EXAMPLE 3 G To the Grignard reagent prepared from 1.71 g. magnesium, 10.3 g. 1-methy1-3-chloromethyl-piperidine, 0.5 ml. ethyl bromide and 50 ml. tetrahydrofuran, the solumelting at 90 92 tion ofl 1110 g. l-oxzod1,2,5,4-tetralhydrg-naphthalerza spirocyc o exane in m tetra y ro uran is a e tinued for 5 hours at room temperature. After standing Preclpltate formed filtered off recrystalhze} from overnight, the mixture is evaporated in vacuo, the residue E 9 yield the corffispondmg hydrochlonde meltmg taken up in benzene and the solution of 25 ml. glacial at 214 W1t.h decomliosmom acetic acid in 25 ml. Water is added dropwise while stir- ..Zissiaatrfirst.3:11.;sis rtitiidi ll rt .1: wd d benzene the Solution of basic with hqueou ammonia. The mixtur: is extr ziiztec l naphthalene be.nZene is slowly added m 30 with diethyl ether, the extract washed with water, dried, gg l g i 5 22223 1 g igg 5:235: 5 filtered and evaporated. The residue is recrystallized from during 45 minutes and the mixture slowly heated and r $32 2 lii ifi lgf ii gyfi th e A r e i ak e n 1?: iii fiuxed for 5 hours After Standing overnight at room 75 ml hot ethyl acetate and isopropanol is added until temperature it is Poured crushed i and 35 dissolution occurs. The solution is then acidified with concentrated hydrochlor 1c geld The organic layer 15 hydrogen chloride in ethyl acetate, the precipitate formed, separated and the aqueous solution extracted with diethyl filtered OE and Washed with ethyl acfltawisopropanol ether. The combined organic solutions are washed with to yield the higher memn" racemate (due to 2 asymi 5% aqueous sodium carbonate and water, dried, filtered metric carbon atoms) f the l-hydroxy-l-K l-methyl-3- and evaporated in vacuo. The residue is distilled and the piperidylmethyl) 1 2 3 4 tetrahydro naphthalene z fraction boiling at l22128/0.3 mm. Hg collected; it represents the l-oxo-l,2,3,4 tetrahydro naphthalene-Z- splrocyclohexane hydrochlondc of the formula spirocyclohexane.

EXAMPLE 2 H0 CH1 HC1 To the Grignard reagent, prepared from 1.71 g. magnesium, 0.5 ml. ethyl bromide, 9.4 g. l-methyl-4-chloroa piperidine and ml. tetrahydrofuran, the solution of 10 g. 1 oxo-l,2,3,4-tetrahydronaphthalene-2-spirocyclohexane in 20 ml. tetrahydrofuran is added dropwise while 50 stirring and cooling. The mixture is stirred for 4 hours at melting at 288 with decomposition.

room temperature, allowed to stand overnight and evapo- The mother liquor B is evaporated in V lhfl residue rated in vacuo. The residue is taken up in benzene and taken up in 50 ethyl acetate, the Solution acidified the solution of 25 ml. glacial acetic acid in 25 ml. water with hydrogen chloride in ethyl acetate, the precipitate is added dropwise while cooling. The organic layer is formed filtered off, triturated with ml. boiling chloroseparated and washed with water. To the combined aqueform and recrystallized from ethyl acetate-isopropanol,

ous solution 5 g. ammonium chloride are added, followed to yield the lower melting racemate of the above comby aqueous ammonia until it is basic. The mixture is expound, melting at 220-221 with decomposition.

tracted with diethyl ether, the extract washed with water,

dried, filtered and evaporated in vacuo. The residue is re- 60 EXAMPLE 4 crystallized from aqueous methanol, to yield the l-hy- According to the method described in the previous droxy-l-(l methyl 4 piperidyl) 1,2,3,4, tetrahydroexamples, the following compounds of Formula II are naphthalene-Z-spirocyclohexane of the formula prepared:

R R R: It, 11 m 11 Salt digit;

OH 0011 11 H (CH2);N(CH3)2 2 5 1101 226 OH H OCH H Same as above 2 5 93-97 OH H OCHZt 5 -115 8% E ii H 2 i-lSl 32201-205 011 11 H 4 1101 193 011 11 0011;. 4 76-78 Du. A mixture.

The starting materials are prepared as follows: To the suspension of 57.2 g. potassium t.-butoxide in 500 ml. benzene, the solution of 36 g. 1-oxo-6-methoxy-l,2,3,4- tetrahydro-naphthalene in 150 ml. benzene is added during 30 minutes while cooling and stirring under nitrol EXAMPLE The mixture of 7 g. l-hydroxy-l-(3'dimethylaminopropyl)-6-meth0xy l,2,3,4 tetrahydro-naphthalene-Z- spirocyclopentane (M.P. 7678), 30 ml. chloroform and 5 ml. acetyl chloride is refluxed for 70 minutes and evap- 5 is g ig g i gg i z g g i g'g i iggs fgg orated in vacuo. he residue is taken up in water, the t ed to 1 W1 War u to room solut1on made basic with 2 N aqueous sodium hydroxide gigg i g 2 rgluxed 2 hour? i stirring g and extracted with diethyl ether. The extract is Washed with water, dried, filtered and evaporated in vacuo. The i gg g g 3 53; igz ggffig gg sig g' f ig gig i z residue is taken up in ethyl acetate, the solution acidified layer se arated and the aqueous solution extracted with wlth hydrogen chlonde ethyl acetate the precipitate diethyl e ther The combined organic solutions are washed formed 0E and .recrystantzed from acetone to yleld with 5% aqueous sodium carbonate and water dried the 1 (3'dlmethylammop p filtered and evaporated in vacuo. The residue is a tetrahydro-naphthalene-2-spirocyclopentane hydrochloride and the fraction boi1ingat160163/0.3 mm. Hg colof the formula lected; it represents the 1-oxo-6-methoxy-1,2,3,4-tetrafi 2 2N(CH3)2HClhydronaphthalene-Z-spirocyclohexane melting at 70-7l.5 m I after recrystallization from methanol.

In the analogous manner, the following starting materials are prepared from equivalent amounts of the corre- CH3) sponding intermediates:

m It (a) l-oxo-5-rnethoxy-1,2,3,4-tetrahydro-naphthalene-Z- e mgat164165 EXAMPLE 6 spirocyclohexane B.P. 138l51/ 0.2 mm. Hg; (b) l-oxo-1,2,3,4-tetrahydro-naphthalene-2-spirocyclo- To the Grlgnard P p from gg pentane, BR 99% mm s1um, 8 g. 3-dimethylamino-propyl chloride, 0.5 ml. ethyl (c) l oxo 6 methoxy 1,23,4 tetrahydro naphtha1ene 2 bromide and 50 ml. tetrahydrofuran, the solution of spirocyclopentane, mm. g. 1 oxo-6-hydroxy-1,2,3,4-tetrahydro-naphthalene-2-sp1- (d) l oxo 2,3 dihydm indene z spimcyclohexane, B'R rocyclohexane in 60 ml. tetrahydrofuran is added dropwise 1104120 03 mm. Hg, MJP e Evhile cooling artid stirring, arlliftstirritng continued hfor7 Another startin material is re ared as follows: To the ours a room empera i E S an g q stirred solution of 86 g. butyr ola tone and 1 kg. chlorowater are added While coohng. and i f followed benzene, p under nitrogen, 500 g anhydrous aluminum by 50 ml. hot benzene. The organic solution is decanted chloride are added portionwise during 2 hours and the mix- "a benlzeile 3 .more The ture is heated to for 20 hours. After cooling it is me organic so ution 1s was ed with water, dried, filtered poured over 2.5 kg. ice and 400 m1. concentrated hydro and evaporated. The residue is recrystalllzed from chlorochloric acid. The organic layer is separated and the aquef ggg gi z g jf g gif i g; & 25; gg i g i ous solution extracted with toluene. The combined organic rocyclohexgne g g k y P a fine solutions are Washed with water, 200 ml. 20% aqueous potassium hydroxide and water again, dried, filtered and 40 (H3H CH1CH2 N (C1192 evaporated in vacuo. The residue is distilled and the fraction boiling at 115 /0.3 mm. Hg collected. According to vapor phase chromatography, it consist of 46-48% 5- i i chloro-, 16 22% 6-chloroand 1624% 7-chloro-1-oxo- HO 1,2,3,4-tetrahydro-naphthalene. On standing at room temmelting at 17 4 t f fif z gi zgg a gg i g zsi fi ggzg gggz ig g sg g It 1s taken up in hot ethyl acetate, and the solut10n mixture consisting of 56 4% and 43 6% acid fied w1th hydrogen chloride in ethyl acetate while chloro 1 oX0 1 2 3 4 tetrah'ydronaphthalene (fraction cooling and st rring. The preclpitate formed is filtered oif The filtrate is a llowed to stand for about 1 week dur- 50 i wafileqdwlth et-hyl acetate tocyleld the corresponding ing which time another precipitate is formed. It is filtered y we on e meltmg at 172474 off and Washed with cooled pentane to yield the mix EXAMPLE 7 ture consisting of 60.9% 5chloro-, 2.9% 6-chloro and 33.7% 7 chloro 1 oxo-1,2,3,4-tetrahydr0-naphthalene n ;-1) t6so1Iulttt)t111O;2 1g.2,13l 4yf ::;$;h y ((1 go 1521;513:1312; f g i rlihe g g f fractgm 5* gl lfig zil d t g spirocyclopentane (M.P. 7678) in the minimum amount 35; at g c h f i n g l i M the of ethyl acetate is slowly acidified by the dropwiseaddi- 5uahrleoo 1ame 1205,1141: h g1: 2 gil lale: ril ltig a tron of hydrogen chloride in ethyl acetate while stirring. 9 f i 2 2 35 z matgrial The precipitate formed after cooling is filtered off and ilds 7 ech1oro 1 0X0 1 2 3 4 tetrah dromag hthalene 60 recrystalhzedfrom acetone to yield the l-(3-d1methyly e 98 99 5 y P amlno-propylidene) 6 methoxy-1,2,3,4-tetrahydronaph- Intii tlgliigil Bis r-eated as Shown above first with Potas thalene-Z-spirocyclopentane hydrochloride; it is identical sium t-butoxide and the resulting potassium compound with the compound obtamed accordmg to Examp 1e with 1,5-di-bromopentane to yield EXAMPLE 3 (e) the mixture of S-chloroand 7-chloro-1-oxo-1,2,3,4- According to the method described in Examples 5-7, tetrahydronaphthalene 2 spirocyclohexane, B.P. the following l-dehydro derivatives corresponding to For- 0.2 mm. Hg. mula II are prepared:

M.P., R1 R2 R3 BA m '11. Salt degrees H H H =CH(CH2)zN(CH3)z 2 5 HCl -191 H OCH3 H Same as above 2 5 H01 189*190 H OCH; OCH3 d 2 5 H01 164-167 H H H 1 5 H01 211-212 1 1 EXAMPLE 9 The mixture of 6.2 g. l-(3-dimethylaminopropylidene)- 6-methoxy 1,2,3,4 tetrahydro-naphthalene-Z-spirocyclohexane, 1 g. platinum oxide and 100 ml. ethanol is hydrogenated at room temperature until 550 ml. hydrogen are absorbed. It is filtered, the filtrate evaporated in vacuo, the residue taken up in diethyl ether, the solution washed with water, dried, filtered and evaporated. The residue is distilled and the fraction-boiling at 162-164/0 .3 mm. Hg collected, to yield the 1-(3-dimethylamino-propyl)-6- methoxy 1,2,3,4 tetrahydro naphthalene-Z-spirocyclohexane of the formula CHsO- It is dissolved in anhydrous diethyl ether and the solution neutralized with hydrogen chloride in ethyl acetate. The precipitate formed is filtered off and washed with diethyl ether, to yield the corresponding hydrochloride melting at l37141.

EXAMPLE To the mixture of 0.5 g. lithium aluminum hydride and 25 ml. anhydrous diethyl ether, the solution of 1.0 g. 1-(N,N dimethylcarbamoyl ethyl) 6 methoxy-1,2,3,4- tetrahydro-naphthalene-2-spirocyclohexane in 5 ml. diethyl ether is added dropwise while stirring and the whole is stirred at room temperature overnight. Hereupon 1.5 ml. ethyl acetate are added, followed by 0.5 ml. water, 1 ml. 5% aqueous sodium hydroxide and 1.5 ml. water. The precipitate formed is filtered 01f, washed with diethyl ether, the filtrate dried and evaporated. The residue is dissolved in the minimum amount of diethyl ether, the solution neutralized with hydrogen chloride in ethyl acetate, the precipitate formed filtered off and washed with diethyl ether, to yield the 1-(S-dimethylamino-propyl)-6-methoxy- 1,2,3,4-tetrahydro-naphthalene-Z-spirocyclohexane hydrochloride melting at 136-139"; it is identical with the product obtained according to Example 9.

The starting material is prepared as follows: To the Grignard reagent prepared from 1.7 g. magnesium, 50 ml. tetrahydrofuran and 11.9 g. 2-benzyloxy-ethyl chloride, the solution of 11 g. 1-oxo-6-methoxy-1,2,3,4-tetrahydro-naphthalene-Z-spirocyclohexane in 20 ml. tetrahydrofuran is added dropwise while stirring and cooling. The mixture is stirred for 5 hours at room temperature and is allowed to stand overnight. It is again cooled in an ice bath, 30 ml. water are added dropwise, followed by the mixture of ml. concentrated hydrochloric acid and 75 ml. water, as well as by 100 ml. diethyl ether. The organic layer is separated, the aqueous solution extracted with diethyl ether and the organic solutions combined. They are washed with water, dried, filtered and evaporated. 10 g. of the residue is taken up in the minimum amount of hot glacial acetic acid, 3.5 g. 10 palladium on charcoal are added and the mixture is hydrogenated at about 25-70 and 50 p.s.i. until the theoretical amount of hydrogen has been absorbed. It is filtered, the filtrate evaporated in vacuo, the residue taken up in diethyl ether, the solution washed with 10% aqueous potassium carbonate, dried, filtered and evaporated, to yield the l-(2-hydroxy-ethyl)-6 methoxy-1,2,3,4-tetrahydro-naphthalene- 2-spirocyclohexane.

To the mixture of 13.7 g. thereof, 50 ml. benzene and 4 g. pyridine, the solution of 9 g. thionyl chloride in 10 ml. benzene is added while stirring and cooling. The mixture is refluxed until the evolution of sulfur dioxide ceases. After cooling, it is washed with water and 1% aqueous potassium carbonate, dried, filtered and evaporated, to yield the 1-(2-chloro-ethyl)-6-methoxy-l,2,3,4- tetrahydro-naphthalene-Z-spirocyclohexane.

13 g. thereof are added portionwise to the solution of 4 g. potassium cyanide, 4 ml. water and 16 ml. ethanol at while stirring. Hereupon the mixture is refluxed for 5 hours and evaporated in vacuo. The residue is taken up in water, the mixture extracted with ethyl acetate, the extract washed with water, dried, filtered and evaporated in vacuo, to yield the 1-(2-cyano-ethy1)- 6-methoxy-1,2,3,4-tetrahydro naphthalene-Z-spirocyclohexane,

The mixture of 11 g. thereof, 12 ml. water, 12 g. sodium hydroxide and 40 ml. ethylene glycol is refluxed for 4 hours and poured into 200 ml. water. The solution obtained is acidified with concentrated hydrochloric acid and extracted with diethyl ether. The extract is washed with water, dried, filtered and evaporated. The residue is taken up in 10% aqueous potassium carbonate, the mixture washed with diethyl ether and acidified with hydrochloric acid. It is again extracted with diethyl ether, the extract dried, filtered and evaporated, to yield the 1-(2-carboxy-ethy1)-6-methoxy 1,2,3,4-tetrahydro-naphthalene-2-spirocyclohexane.

The mixture of 5.5 g. thereof, 25 ml. benzene and 2.5 ml. thionyl chloride is refluxed for 1 hour and evaporated in vacuo. To the residue benzene is added, which again is distilled olf. The residue is dissolved in 25 ml. benzene, and the solution added dropwise to the mixture of 3.0 g. dimethylamine in 25 ml. benzene while stirring and keeping the temperature below 20. The mixture is stirred overnight at room temperature, and the precipitate formed filtered off. The filtrate is evaporated in vacuo, the residue taken up in diethyl ether, the solution washed with water, 2 N aqueous hydrochloric acid, 2 N aqueous sodium hydroxide and water, dried, filtered and evaporated, to yield the 1-(N,N-dimethylcarbamoylethyl)-6-methoxy 1,2,3,4 tetrahydro naphthalene-2- spirocyclohexane, which is used as such without further purification.

The above-mentioned chloroethyl compound may be reacted with an excess of di-n-butylamine, pyrrolidine, unorpholine or l-methyl-piperazine, in order to yield the 1-(2-di-n-, butylamino-, pyrrolidino-, morpholinoor N- methyl-piperazino-ethyl)-6 methoxy-l,2,3,4-tetrahydronaphthalene-2-spirocyclohexane.

The above-mentioned cyano compound may also be reduced as shown above for the dimethylamide, to yield the 1-(3-aminopropyl)-6 methoxy-1,2,3,4-tetrahydronaphthalene-2-spirocyclohexane.

EXAMPLE 11 Preparation of 10,000 tablets each containing 100.0 mg. of the active ingredient:

Purified water, q.s.

Procedure All the powders are passed through a screen with openings of 0.6 mm. Then the drug substance, lactose, talcum, magnesium stearate and half of the starch are mixed in a suitable mixer. The other half of the starch is suspended in 65 ml. water and the suspension added to the boiling solution of the polyethylene glycol in 260 ml. water. The paste formed is added to the powders which are granulated, if necessary, with an additional amount of water. The granulate is dried overnight at 35, broken on a screen with 1.2 mm. openings and compressed into tablets using concave punches with 10.3 mm. diameter, uppers bisected.

13 I claim: 1. An analgetic pharmaceutical composition comprising an analgetically effective amount of a compound having the formula in which Ph is 1,2-phenylene, (lower alky1)-1,2-phenylene, (hydroxy)-l,2-phenylene, monoor di-(lower alkoxy)-l,2-phenylene, (halogeno)-1,2-phenylene or (triifluoromethyl)-1,2-phenylene wherein the lower alkyl and alkoxy groups contain up to 4 carbon atoms, alk is methylene, 1,2-ethylene or 1,3-propy1ene, B is 1,4-buty1- ene, 1,5-pentylene or 1,5-pent-2-enylene, R is hydrogen or hydroxy, alk is 1,2-ethylene, 1,2- or 1,3-propylene, Am is di-lower alkylamino or lower alkyleneimino or alk -Am together represents 1-methyl-3-piperidy1, 1- methyl-4-piperidyl, 1-methy1-3-piperidyl methyl or 1- methytl-4-piperidylmethyl, the l-dehydro derivatives of said compounds of the above formula, wherein R forms an additional bond to alk or a therapeutically acceptable acid addition salt thereof, together with a pharmaceutical excipient.

2. A composition as claimed in claim 1, wherein the compound is that of the formula References Cited UNITED STATES PATENTS 9/ 1969- Kaltenbronn 424230 OTHER REFERENCES Derwent Farmdoc. No. 35,687, Great Britain Pat. No. 1,140,990, pp. 279-282, published I an. 22, 1969.

JEROME V. GOLDBERG, Primary Examiner V. D. TURNER, Assistant Examiner US. Cl. X.R.

424--244, 246, 248, 250, 274, 330; 260239 B, 243 B, 247, 268 R, 293.66, 326.8, 570.5 R, 570.5 P, 570.8 

